Original Article

Journal of Child Neurology

1-8
Identifying Clinical Clues in Children With ª The Author(s) 2020
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Global Developmental Delay / Intellectual DOI: 10.1177/0883073820977330
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Disability With Abnormal Brain Magnetic
Resonance Imaging (MRI)

Abdullah Alamri, MBBS1, Yaser I. Aljadhai, MBBS2, Abdullah Alrashed, MBBS2,

Bandar Alfheed, MBBS2, Roba Abdelmoaty, MBBS3, Shoaa Alenazi, MBBS3,
Aqeela Alhashim, MBBS3 , and Ruba Benini, MD, CM, PhD4

Abstract
Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI),
although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature
suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative
neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with
global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would
benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary
care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed
clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327,
67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and
radiologic evaluations. Mean age was 37.9 months (+32.5 standard deviation) and 116 were males (53%). Motor deficits were
predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most
prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus
(50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability
(3, 100%) as well as those with visual and hearing impairment (P < .05). The presence of facial dysmorphisms (57/71, P ¼ .02);
cranial nerve abnormalities (79/100; P ¼ .007) and abnormal reflexes (16, P ¼ .01) on examination also correlated significantly with
increased MRI abnormalities.

Keywords
developmental delay, brain magnetic resonance imaging (MRI), neuroimaging, intellectual disability

Received June 23, 2020. Received revised October 16, 2020. Accepted for publication November 7, 2020.

Global developmental delay is defined as a significant delay in

2 or more developmental domains, including gross or fine
motor, speech/language, cognitive, social/personal, and activi-
ties of daily living and is thought to predict a future diagnosis of
intellectual disability.1 According to the American Association 1
Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal
on Intellectual and Developmental Disability (AAIDD), intel- University, Dammam, Saudi Arabia
2
Department of Neuroimaging and Intervention, Medical Imaging
lectual disability is defined as “a disability characterized by
Administration, King Fahad Medical City, Riyadh, Saudi Arabia
significant limitations both in intellectual functioning and in 3
Pediatric Neurology Department, National Neuroscience Institute, King
adaptive behavior as expressed in conceptual, social, and prac- Fahad Medical City, Riyadh, Saudi Arabia
tical adaptive skills.2 4
Pediatric Neurology Division, Sidra Medicine, Doha, Qatar
The prevalence of global developmental delay/intellectual
Corresponding Author:
disability is estimated to be between 1% and 3%,3 with a wide Ruba Benini, MD, CM, PhD, Pediatric Neurology Division, Sidra Medicine,
range of etiologies including genetic/metabolic, in utero expo- Doha, Qatar.
sure to toxins or infections, perinatal asphyxia, prematurity, Email: ruba.benini@mail.mcgill.ca
2 Journal of Child Neurology XX(X)
neonatal infections, and postnatal acquired causes.4 The eva-
luation of a child with global developmental delay/intellectual
disability should always begin with a comprehensive history
and physical examination including a thorough neurologic and
developmental assessment.3,5,6 This approach by itself has
been shown to yield a diagnosis in up to 40% of cases and
cannot be replaced by laboratory or radiologic investiga-
tions.6,7 Although a number of clinical variables (antenatal
exposure to toxins, microcephaly, focal motor findings, and
absence of autistic features) have been shown to increase the
yield of finding an etiologic diagnosis in the evaluation of a
child with global developmental delay/intellectual disability,8
the relationship between these variables and neuroimaging
findings remains to be clarified.
With the advent of imaging techniques, magnetic resonance
imaging (MRI) has been increasingly used in the evaluation of
global developmental delay/intellectual disability. However,
the yield of finding abnormalities ranges from as low as 9%
if used merely as a screening tool to up to 80% in some studies
if used in selected patients.9,10 MR spectroscopy, by measuring
various brain metabolites, offers additional information and
can increase the yield in finding a diagnosis for global devel-
opmental delay / intellectual disability especially in neurome-
tabolic cases.10,11 In children with global developmental delay/
intellectual disability, common abnormalities found on brain
MRI have included cortical malformations, abnormal cere-
brospinal fluid spaces, corpus callosum dysplasia or agenesis,
abnormal basal ganglia size or signal, as well as cerebellar and
brain stem anomalies.10
Although MR imaging can be useful in the evaluation of
children with global developmental delay/intellectual disabil-
ity, aside from cost, there are other important considerations
that must be addressed. MR imaging is usually a lengthy pro-
cedure during which multiple radiologic sequences are taken in
various dimensions, thus requiring a cooperative patient that
can tolerate lying still for 60-90 minutes within the confined
space of the machine. General anesthesia is often needed to
sedate pediatric patients in order to reduce motion artifacts and
obtain good-quality MRIs. Although procedural sedation is
used extensively in the pediatric population for surgical and
nonsurgical purposes, there is increasing evidence from the
literature that exposure of the developing brain to sedating
agents is not benign and may have long-term consequences
on neurodevelopmental outcomes, especially in children
exposed to general anesthesia.12,13 Some studies have further
elucidated that exposure of infants to general anesthesia leads
to specific neuropsychological adverse effects primarily affect-
ing language and abstract reasoning.14 Furthermore, there is
some suggestion that general anesthesia could be associated
with regional volumetric alterations in brain structure.15
Although MR imaging can be essential in guiding further
investigations or reaching a diagnosis that has important
implications for both the patient and the family, considering
this recent data, it becomes essential for physicians evaluating
children with global developmental delay/intellectual disabil-
ity to be conscious of these potentially long-term side effects
of sedation especially in this vulnerable population. There are
extensive guidelines in the literature on what diagnostic mod-
alities should be used in the evaluation of children with global
developmental delay/intellectual disability, but evidence-
based guidelines on which selected patients would be more
likely to benefit from MRI in reaching a diagnosis remains
sparse. The goal of this retrospective study is to address this
question by highlighting which clinical clues (historical and
physical examination) are more likely to increase the yield of
finding MRI abnormalities in the evaluation of children with
global developmental delay/intellectual disability in order to
avoid unnecessary harmful complications related to
anesthesia.
Method
Study Design and Patient Population
This study was a retrospective chart review analysis of all children
referred to the Pediatric Neurology Department at King Fahad Med-
ical City (KFMC) in Saudi Arabia for evaluation of global develop-
mental delay or intellectual impairment between 2014 and 2017
inclusive and who had a brain MRI done at some point during their
workup.
Inclusion criteria
 Age <12 years
 Referral for evaluation of global developmental delay or intel-
lectual disability
 Documented clinical history and physical examination at first
clinic evaluation
 Brain MRI (with or without MRS) done as part of the workup
Exclusion criteria
 Children referred for evaluation of isolated motor or speech
delay
 Children referred for evaluation of autism spectrum disorders
 Children who did not have brain MRI done as part of their
evaluation
Patients with delays in 2 or more developmental spheres were
classified to have global developmental delay if less than 5 years of
age and intellectual disability if more than 5 years of age. Both groups
of patients were grouped into one study group classified as global
developmental delay/intellectual disability, and all data analysis was
performed on this group.
The charts of all patients were reviewed, and a myriad of clinical
and historical variables were extracted from the first detailed docu-
mented neurologic clinic visit evaluation. In addition to demographic
data and age at initial evaluation, the presence of perinatal/postnatal
risk factors such as a history of prematurity, complicated delivery,
perinatal asphyxia, neonatal encephalopathy, neonatal seizures, neo-
natal hyperbilirubinemia, or prolonged admission to the neonatal
intensive care unit were extracted. The presence of other comorbid-
ities as documented in the history including the presence or absence of
swallowing difficulties, hearing or visual impairment, behavioral
symptoms (hyperactivity, aggressive behavior), seizures, as well as
a history of recurrent medical admissions was also noted. Seizures
were further classified into focal versus generalized based on history
and, if present, electroencephalographic (EEG) findings. Family
Alamri et al 3

history variables including the presence of consanguinity, recurrent Table 1. Sociodemographics and Clinical Characteristics of Patients
miscarriages, sudden infant deaths, as well as the presence of neuro- With Global Developmental Delay / Intellectual Disability (N ¼ 218).
logic disorders (seizures, developmental delay, intellectual impair-
ment) in first-degree relatives was also noted. Details of the Characteristic Mean + SD or n (%)
developmental delay were classified based on which developmental Age, mo, mean + SD 37.9 + 32.5
sphere was affected (motor, language, social/communicative, cogni- Gender
tive) and if a predominance was identified. Physical examination find- Female 102 (47%)
ings were extracted focusing on the presence or absence of abnormal Male 116 (53%)
head size as well as non-neurologic signs (musculoskeletal abnorm- Nationality
alities, neurocutaneous findings, cardiac abnormalities, hepatospleno- Saudi 215 (99%)
megaly, spinal dysraphism). The presence or absence of dysmorphic Others 3 (1%)
features as documented in the chart was also extracted. Abnormalities Predominance of the developmental delay
Motor 122 (56)
on the neurologic examination were subdivided to identify cranial
Language 12 (6)
nerve abnormalities, abnormalities on the motor examination (hypo- Social/ Cognitive 3 (1)
tonia, spasticity, rigidity, weakness, focal deficits), increased or No predominance 81 (37)
decreased deep tendon reflexes, gross sensory anomalies, and cerebel- Brain MRI
lar and gait anomalies (including the presence of ataxia). A summary Abnormal 153 (70)
of all these sociodemographic and clinical findings is summarized in Normal 65 (30)
Table 1. Presence of early risk factors (history)
As per institution protocol, all patients had received procedural Prenatal risk factors 33 (15)
sedation for their MRI study, the majority of which were done without Perinatal risk factors 38 (17)
contrast. For each patient, the brain MRIs were reviewed by a board- Neonatal risk factors 80 (36)
Comorbidities
certified pediatric neuroradiologist and classified into normal versus
Seizures 75 (34)
abnormal. Abnormal brain MRI findings were further classified into Swallowing difficulties 33 (15)
12 major categories to identify specific anomalies related to the corpus Vision problems 33 (15)
callosum, ventricles, pituitary gland, optic pathway, olfactory path- Hearing problems 14 (6)
way, cortical development, cerebellum, white matter, basal ganglia, Family history
thalamus, hippocampus, and brainstem (Table 2). The presence of Consanguinity 128 (59)
these individual abnormalities were further correlated with the clinical Seizures 22 (10)
variables extracted (Table 3). Global developmental delay / intellectual 35 (16)
Although the clinical data extracted for this retrospective chart disability
review was based primarily on the initial clinic visit evaluation, for SIDs and miscarriages 12 (6)
Other neurologic disorders 15 (7)
patients for whom an etiologic diagnosis had been attained and docu-
Head circumference
mented during the study period, this information was also extracted. Normocephalic 126 (58)
Abnormal HC 92 (42)
Statistical Analysis Microcephalic 80 (97)
Macrocephalic 12 (13)
The clinical data were collected and entered into an electronic data- Non-neurologic physical findings
base using SPSS 22.0 software. Demographic and clinical character- Abnormal systemic findings 97 (45)
istics of the studied patients were reported as mean (standard Facial dysmorphism 71 (33)
deviation). Additionally, categorical variables were reported as counts Neurologic examination
(percentage). All analyses were performed using SPSS 22.0 software Normal 32 (15)
Abnormal 186 (85)
(SPSS Inc, Chicago, IL) package; 2-tailed P value of less than .05 was
Mental status 31 (17)
considered significant. Cranial nerves 16 (8)
Motor examination 175 (94)
Reflexes 100 (54)
Cerebellar examination 12 (6)
Results Gait 19 (10)
All referral requests to the outpatient pediatric neurology Final Diagnosis
department were screened between 2014 and 2017. Of the Unknown 115 (53)
Confirmed 103 (47)
1492 new clinic visits, 327 patients had been referred for eva- Genetic 79 (77)
luation of global developmental delay/intellectual disability. Acquired/other 24 (13)
After applying the inclusion criteria and excluding patients
with incomplete clinical and/or radiologic data, 218 subjects Abbreviations: HC, head circumference; MRI, magnetic resonance imaging;
SD, standard deviation; SIDs sudden infant deaths.
were enrolled into the analysis, of whom 116 (53%) were male
(Table 1). The mean age of the study group at the time of the
first clinic evaluation was 37.9 months (+32.5 standard 218 (56%), whereas in 81/218 (37.2%) of patients, the predo-
deviation). minance could not be determined. Associated comorbidities
Although all patients had a global developmental delay, including the presence of seizures, swallowing difficulties,
motor deficits were predominant in most of the subjects 122/ visual and hearing impairment were observed in 34%, 15%,
4 Journal of Child Neurology XX(X)

Table 2. Summary of Magnetic Resonance Imaging (MRI) developmental delay / intellectual disability with nonspecific
Abnormalities (N ¼ 153). white matter abnormalities for which an etiologic diagnosis had
MRI Findings n (%)
been confirmed, 82% (14/17) were associated with a confirmed
neurogenetic disorder and the remaining 18% (3/17) were asso-
Corpus callosum ciated with malformations of cortical development.
Abnormal 77 (50.3) Other common MRI abnormalities included corpus callo-
Absent 4 (2.6) sum dysgenesis (77/153, 50%) and incomplete inversion/
Partial agenesis 13 (8.5)
malrotation of hippocampus (50/153, 33%). Thin/hypoplastic
Thin / hypoplastic 60 (39.2)
Ventricles corpus callosum was a more common finding (60/77) than
Abnormal 46 (30) complete or partial agenesis (17/77), and in the cohort of
Colpocephaly 9 (5.9) patients with a confirmed diagnosis and corpus callosum
Generalized ventriculomegaly 31 (20.3) abnormalities (24), the former finding was seen equally in both
Other: eg, hydrocephalus 6 (3.9) the genetic (12/24) and the nongenetic/acquired (12/24)
Pituitary abnormalities 5 (3.3) groups.
Optic pathway 5 (3.3)
Abnormalities of the cerebral ventricles, cerebellum, and
Olfactory pathway 0 (0)
Malformations of cortical development 14 (9.2) basal ganglia were noted in 46 (30%), 34 (22%), and 21
Cerebellum abnormalities 34 (22.2) (14%), respectively, of all patients with global developmental
Brain stem abnormalities 14 (9.2) delay/intellectual disability. Cortical malformations and brain-
White matter stem abnormalities were less common and represented 9% of
Abnormal 104 (68) the abnormalities noted (Table 2). Brainstem abnormalities
Nonspecific 31 (20.3) were suggestive of a malformative etiology in the majority of
Delayed myelination 19 (12.4)
cases (10/14) and included findings such as dysplastic medulla,
Dysmyelination / leukoencephalopathy 12 (7.8)
Periventricular leukomalacia 23 (15) molar tooth malformation, hypoplastic pons, and were occa-
Volume loss 19 (12.4) sionally associated with other findings such as holoprosence-
Basal ganglia abnormalities 21 (13.7) phaly or microcephaly (2).
Abnormal thalami 18 (11.8) In the 21 patients with basal ganglia abnormalities, MRI
Hippocampal abnormalities changes were suggestive of a neurometabolic entity in the
Incomplete inversion / malrotation 50 (32.7) majority of cases (12/21, 57%) whereas in the remaining 9
Mesial temporal sclerosis 0 (0)
cases the abnormalities were indicative of a neurovascular
(6), malformative (1), infectious (1), and nonspecific (1) etiol-
ogy. Ninety-two percent (11/12) of the patients with suspected
15%, and 6%, respectively. The majority of patients were nor-
neurometabolic disorders on MRI due to basal ganglia abnorm-
mocephalic (58%, 126/218), but those with abnormal head
alities were later confirmed genetically and included disorders
sizes (42%, 92/218) were more likely to be microcephalic
such as MEGDEL syndrome (1), infantile neuroaxonal dystro-
(87%, 80/92) than macrocephalic (13%, 12/92). Facial dys- phy type 1 due to homozygous PLA2G6 mutations (4), Aicardi
morphisms were noted in approximately a third of patients Goutières syndrome due to homozygous RNASEH2B muta-
(71/218, 33%) with the majority of patients having an abnormal tions (1), Coffin Siris syndrome due to SMARCA4 gene muta-
neurologic examination (186/218, 85%). Family history tion (1), and mitochondrial disorders (homozygous mutations
revealed that consanguinity was prevalent and positive in in FBXL4 [1], HIBCH [1], SERAC1 [1]). On the other hand,
59% of cases. the majority of the abnormalities noted in the thalamus (78%,
Of the 218 patients reviewed in this study, an etiologic 14/18) were suggestive of previous vascular insults (sequelae
diagnosis for the global developmental delay/intellectual dis- of perinatal asphyxia).
ability was available in 103 patients (47%) at the time of the Correlation of the various clinical variables with the pres-
study. Genetically confirmed etiologies accounted for the ence of MRI abnormalities revealed that children with predo-
majority of these cases (79/103, 77%), with nongenetic/ minant motor developmental delay were more likely to have
acquired causes such as prematurity, perinatal asphyxia, and abnormal MRI findings 84/122 (69%, P ¼ .03). Of the
TORCH infections being less common (24/103, 13%). 33 patients with visual impairment, 28 of them (85%) had
Review of MRI studies revealed abnormalities in up to 70% associated MRI abnormalities (P < .05) as did all 14 patients
of children with global developmental delay/intellectual dis- with hearing impairment (100%) (P ¼ .01) (Table 3).
ability (153/218), with white matter abnormalities representing Approximately one-third of patients (75/218, 34%) with
the most common abnormal findings in 68% of children global developmental delay/intellectual disability also experi-
(104/153). White matter abnormalities included nonspecific enced seizures, with the majority (77%, 58/75) of these pre-
changes, hypomyelination, dysmyelination/leukoencephalopa- senting with abnormal MRI findings (Table 3). Abnormal MRI
thy, periventricular leukomalacia, and volume loss, with non- findings were similarly prevalent in patients with focal (14/18,
specific white matter changes being the most frequent (31/104; 78%, P ¼ .47) and generalized seizures (42/54, 78%, P ¼ .16)
30%) (Table 2). In the cohort of patients with global without reaching statistical significance.
Alamri et al 5

Table 3. Correlation of Clinical Characteristics With Abnormal are referred to developmental pediatrics for evaluation.
Magnetic Resonance Imaging (MRI) Findings. Although MR imaging is often recommended as either first tier
Abnormal
or second tier in the investigation of children with global devel-
Clinical Characteristics Brain MRI, n (%) P value opmental delay/intellectual disability, the literature on the yield
of this diagnostic modality is varied with some quoting a yield
Predominance of the developmental delay as high as 80%16,17 and others as low as 7.5%. 10 Similar to
Motor* 84 (68.9) .013 what has been previously reported in the literature,10,16-18 our
Speech 4 (33.3)
present study has shown that the yield of an abnormal MRI in
Social/cognitive* 3 (100.0)
No predominance 62 (76.5) nonselected patients with global developmental delay / intel-
Prenatal risk factors: Yes 22 (66.7) .632 lectual disability to be relatively high with abnormalities noted
Perinatal risk factors: Yes 30 (78.9) .194 in up to 70% of cases.
Neonatal risk factors: Yes 56 (70.0) .964 A number of clinical variables were identified as predictors
History of NICU admission: Yes 45 (71.4) .798 of an abnormal MRI. For example, children with motor delay
Comorbidities as a predominant feature were more likely to have an abnormal
Seizure 58 (77.3) .095
brain MRI as compared to children with predominant deficits
Swallowing 20 (60.6) .192
Vision impairment* 28 (84.8) .046 in other developmental spheres such as cognition, language,
Hearing impairment* 14 (100.0) .012 and social/communicative skills. This finding may be partly
Head circumference explained by the fact that the average age at evaluation in this
Abnormal 65 (70.7) .897 cohort was around 37.9 months (+32.5 standard deviation), an
Microcephalic 55 (68.8) .725 age where objective and detailed cognitive assessments are
Macrocephalic 10 (83.3) .186 difficult to complete, especially during a first clinic evaluation.
Non-neurologic clinical findings
Other important predictors of abnormal MRI findings
Abnormal 74 (76.3) .078
Dysmorphism* 57 (80.3) .024 included the presence of hearing and visual impairment, dys-
Neurologic exam findings morphic features, or abnormalities on the neurologic examina-
Abnormal 135 (72.6) .062 tion (specifically cranial neuropathies or abnormal reflexes, the
Mental status 21 (13.7) .748 latter suggestive of an abnormal motor examination) (Table 3).
Cranial nerves* 16 (10.5) .007 These observations are in accordance with recent studies
Motor 128 (73.1) .054 demonstrating that the diagnostic yield of MRI in patients with
Reflexes* 79 (79) .009
global developmental delay/intellectual disability and addi-
Cerebellar 9 (5.9) .708
Gait 13 (8.5) .86 tional features is higher (89%) than in children with only devel-
opmental delay (11%).18
Abbreviation: NICU, neonatal intensive care unit. The presence of dysmorphic features often heralds an under-
*Statistical significance.
lying genetic etiology and has been shown to be an important
predictor of abnormal MRI findings.8,18 This is particularly
A number of physical signs were significantly correlated interesting in our cohort considering the high rate of consan-
with an abnormal brain MRI including the presence of facial guinity (58%) and the fact that the majority of patients with an
dysmorphic features (57/71, 80%, P ¼ .02), cranial nerve established diagnosis and abnormal MRI findings (70%, 51/73)
abnormalities (16/153, 10.5%, P < .01), and abnormal deep had a confirmed genetic etiology.
tendon reflexes (79/100, 79%, P < .01) (Table 3). Interesting, in contrast to other studies demonstrating that
Other historical elements including perinatal and neonatal the presence of seizures increases the diagnostic yield of the
risk factors, family history, and consanguinity did not yield a MRI 18, this finding was not reproduced in this cohort. Despite
significant statistical correlation with the MRI findings. Simi- the fact that the majority of patients with global developmental
larly, other physical findings including head circumference had delay/intellectual disability and abnormal MRI findings had
no statistically predictive correlation with abnormal MRI find- seizures (77%) as an associated comorbidity, this did not reach
ings although the majority of patients with global developmen- statistical significance, even when seizures were stratified as
tal delay/intellectual disability and microcephaly/ focal vs generalized. Similarly, for abnormal head circumfer-
macrocephaly had MRI abnormalities (65/92, 71%) (Table 3). ence, 70% of patients with global developmental delay/intel-
lectual disability and microcephaly/macrocephaly had
abnormal MRI findings, but this also did not reach statistical
Discussion significance.
Global developmental delay/intellectual disability has a wide The pattern and prevalence of the different abnormal MRI
range of etiologies and is an important reason for referral to findings in children with global developmental delay/intellec-
pediatricians and pediatric neurologists. At our center, global tual disability has varied across different studies. In a large
developmental delay/intellectual disability represented 20% of retrospective study, Momen et al in 201116 reported that in
all new referrals to pediatric neurology although this number is 580 developmentally delayed children, findings included non-
likely to be an underestimate as it does not capture patients that specific in 6.6%, congenital and developmental brain
6 Journal of Child Neurology XX(X)
anomalies in 6.7%, recognizable syndromes in 0.5%, neuro-
vascular diseases or trauma in 37.6%, and metabolic or neu-
rodegenerative diseases in 7.2%. In another study by Koul
et al, among 110 children with global developmental delay,
81.3% had abnormal brain MRI, with imaging abnormalities
ranging from nonspecific white matter changes, age-related
changes, mild volume loss, to cerebral dysgenesis.17 In this
present study, we have described similar patterns and found
white matter abnormalities as well as corpus callosal dysgen-
esis/hypoplasia to be the most common anomalies seen in
children with global developmental delay/intellectual
disability.
White matter abnormalities were seen in 48% of patients
with global developmental delay/intellectual disability in our
study, representing 68% of all the MRI abnormalities observed.
The most common white matter changes noted were nonspe-
cific and were seen in 15% (31/218) of patients with global
developmental delay/intellectual disability in this cohort, con-
sistent with findings from other studies.17 Nonspecific white
matter changes have been described in patients who are imaged
for a variety of indications, including neurodevelopmental
disorders, seizures, migraines, and endocrine disorders.19,20
They can be seen in up to 4% of children presenting with head-
aches19 as well as in up to 13% of children with developmental
delay.17 The clinical and pathophysiologic significance of
these nonprogressive white matter changes remains unclear,
and further studies are needed to try to elucidate the signifi-
cance of these findings in children with neurodevelopmental
disabilities. It is interesting to note, however, that among the
patients in this study with global developmental delay/intellec-
tual disability and an established diagnosis that had nonspecific
white matter changes on their MRI, 80% had a confirmed
genetic etiology, thus raising the possibility as to whether these
presumably nonrelevant findings may be linked to a genetic
predisposition.
Corpus callosum abnormalities were the second most com-
mon abnormalities seen, representing half of the abnormal MRI
findings and seen in 35% of the patients with global develop-
mental delay/intellectual disability (Table 3). Developmental
anomalies of the corpus callosum can range from a hypoplastic
corpus callosum to complete agenesis and have been closely
linked to neurodevelopmental disabilities. In our cohort, thin/
hypoplastic corpus callosum was more prevalent than agenesis/
partial agenesis, and in children with an established diagnosis,
was seen equally in both genetic and nongenetic etiologies.
Anomalies of the corpus callosum can arise from genetic,
infectious, vascular, or toxic etiologies.21 Genetic syndromes
have been shown to account for up to 10%-15% to up to 37% of
patients with agenesis of the corpus callosum ranging from
monogenic disorders, chromosomal copy number variants, and
recognizable clinical syndromes.21,22 Patients with anomalies
of the corpus callosum have been reported to have develop-
mental delays that range from normal-mild in 30% of cases to
moderate-severe in up to 71% of patients.23
Incomplete hippocampal inversion/malrotation was also
noted in 23% of patients. Incomplete hippocampal inversion
is a common developmental brain anomaly characterized by
a rounded, vertically oriented and medially positioned hip-
pocampus with an associated deep collateral sulcus.24,25
Incomplete hippocampal inversion has been mostly
described in relation to epilepsy, specifically temporal lobe
epilepsy, and often occurs with other malformations of cor-
tical development including corpus callosum agenesis, with
a prevalence of 30%-50%.24-27 Despite this, there has been
no causal relationship identified between incomplete hippo-
campal inversion and epilepsy and this hippocampal variant
has also been reported in healthy subjects, albeit at a much
lower frequency. 25,26,28 In children with epilepsy and
incomplete hippocampal inversion, cognitive impairment
has been shown not to be directly related to the presence
of incomplete hippocampal inversion itself but to the asso-
ciated morphologic and functional changes that may occur
in the prefrontal cortex.29 Although incomplete hippocampal
inversion has been postulated to represent a biomarker for
abnormal brain development, 30 its clinical relevance in
patients with global developmental delay/intellectual dis-
ability remains unclear.
Finally, although basal ganglia abnormalities were only
seen in 14% of children with global developmental delay/intel-
lectual disability, the majority were suggestive of a
neurometabolic/neurogenetic entity that was confirmed on fur-
ther genetic testing. On the other hand, thalamic abnormalities
were more likely to be associated with neurovascular insults/
sequala.
Altogether, this study has identified clinical features that
could serve as important clinical biomarkers to guide the phy-
sician in identifying which children with global developmental
delay/intellectual disability would benefit from a brain MRI on
their initial clinic evaluation. These findings highlight that
children with global developmental delay/intellectual disability
that have a predominant motor delay, dysmorphic features,
abnormalities on the neurologic examination, and associated
hearing and vision impairments could potentially benefit from
a brain MRI as part of their workup. Although the predictive
value of seizures and microcephaly/macrocephaly did not
reach statistical significance, these clinical variables were pre-
valent in children with abnormal MRI findings and should also
be taken into consideration.
There were a number of limitations in this study that need to
be recognized. To begin with, this study only evaluated patients
for whom neuroimaging data were available (218 of the 327
patients). This may have led to a selection bias considering that
neurologists most likely requested MRIs for patients based on
abnormal clinical findings. This being said, the findings of this
study are nevertheless clinically relevant since they highlight
which specific clinical findings are most likely related to an
abnormal MRI.
Inherent to any retrospective chart review analysis, the clin-
ical data collected was limited by the details of the clinical
documentation, and as such, specific individual clinical details
could not be captured in a statistically meaningful manner. For
example, specific details of dysmorphic features or motor
Alamri et al
abnormalities could not be captured individually. To overcome
this limitation, clinical details had to be classified in groups, for
example, as “presence or absence of dysmorphic features” or as
“abnormalities on motor examination.” Future prospective
studies may be needed to further delineate which specific
motor abnormalities or dysmorphic features may more likely
increase the yield of neuroimaging abnormalities.
Finally, because of the retrospective nature of the study,
correlation between the yield of the MRI findings and the
etiologic diagnosis in this cohort of patients with global devel-
opmental delay/intellectual disability was incomplete. Consid-
ering that only clinical variables from the first clinical
evaluation were extracted for the purpose of this study, the
final etiologic diagnosis was not available for all patients at
the time of data collection and could not be correlated accu-
rately to the yield of the MRI findings. Nevertheless, the spe-
cific MRI findings in the cohort that did have an established
diagnosis were revealing as discussed above.
In conclusion, despite the limitations discussed above, this
study has demonstrated that cranial MRI is a powerful tool in
evaluating pediatric patients with global developmental delay/
intellectual disability and can be of relatively high yield with
careful selection of patients. More large-scale prospective multi-
center studies are required to confirm and provide more clues for
better utilization of this modality and to avoid unnecessary pro-
cedural sedation in those in whom the yield is expected to be low.
Author Contributions
AAlamri contributed to the design of the project, acquisition/analysis/
data and drafting and approving the written manuscript. YA contrib-
uted to the design of the project, acquisition, analysis and interpreta-
tion of radiological data. AAlrashed and BA contributed to the
acquisition, analysis and interpretation of radiological data. RA and
SA contributed to the acquisition, analysis and interpretation of clin-
ical data. AAlhashim contributed to the design of the project, analysis/
interpretation of data and drafting/approving the written manuscript.
RB as the senior/corresponding author contributed to the conception/
design of the project, acquisition/analysis/interpretation of data, draft-
ing and finalizing the manuscript.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
ORCID iD
Aqeela Alhashim, MBBS https://orcid.org/0000-0002-1343-6298
Ruba Benini, MD, CM, PhD https://orcid.org/0000-0002-0603-803X
Ethical Approval
The authors received institutional review board approval from King
Fahad Medical City, Riyadh, Saudi Arabia (IRB00010471).
7
References
1. Shevell M, Ashwal S, Donley D. Practice parameter: evaluation
of the child with global developmental delay: Report of the qual-
ity standards subcommittee of the American Academy of Neurol-
ogy and the Practice Committee of the Child Neurology Society.
Neurology. 2003;60(3):367-380.
2. Schalock RL, Luckasson RA, Shogren KA. The renaming of
mental retardation: Understanding the change to the term
intellectual disability. Intellect Dev Disabil. 2007;45(2):
116-124.
3. Moeschler JB, Shevell M, Saul RA. Comprehensive evaluation of
the child with intellectual disability or global developmental
delays. Pediatrics. 2014;134(3):e903-18.
4. Wilska ML, Kaski MK. Why and how to assess the aetiologi-
cal diagnosis of children with intellectual disability/mental
retardation and other neurodevelopmental disorders: Descrip-
tion of the Finnish approach. Eur J Paediatr Neurol. 2001;
5(1):7-13.
5. Silove N, Collins F, Ellaway C. Update on the investigation of
children with delayed development. J Paediatr Child Health.
2013;49(7):519-525.
6. Jimenez-Gomez A, Standridge SM. A refined approach to evalu-
ating global developmental delay for the international medical
community. Pediatr Neurol. 2014;51(2):198-206.
7. Majnemer A, Shevell MI. Diagnostic yield of the neurologic
assessment of the developmentally delayed child. J Pediatr.
1995;127(2):193-199.
8. Shevell MI, Majnemer A, Rosenbaum P, Abrahamowicz M.
Etiologic yield of subspecialists’ evaluation of young children
with global developmental delay. J Pediatr. 2000;136(5):
593-598.
9. McDonald L, Rennie A, Tolmie J, Galloway P, McWilliam R.
Investigation of global developmental delay. Arch Dis Child.
2006;91(8):701-705.
10. Verbruggen KT, Meiners LC, Sijens PE, Lunsing R, Jvan Spron-
sen FJ, Brouwer OF. Magnetic resonance imaging and proton
magnetic resonance spectroscopy of the brain in the diagnostic
evaluation of developmental delay. Eur J Paediatr Neurol. 2009;
13(2):181-190.
11. Martin E, Keller M, Ritter S, Largo RH, Thiel T, Loenneker T.
Contribution of proton magnetic resonance spectroscopy to the
evaluation of children with unexplained developmental delay.
Pediatr Res. 2005;58(4):754-760.
12. Vutskits L, Davidson A. Update on developmental anesthesia
neurotoxicity. Curr Opin Anaesthesiol. 2017;30(3):337-342.
13. Nestor KA, Zeidan M, Boncore E. Neurodevelopmental outcomes
in infants undergoing general anesthesia. J Pediatr Surg. 2017;
52(6):895-900.
14. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences
in language and cognitive function after childhood exposure to
anesthesia. Pediatrics. 2012;130(3):e476-e485.
15. Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition
and brain structure following early childhood surgery with
anesthesia. Pediatrics. 2015;136(1):e1-12.
8 Journal of Child Neurology XX(X)
16. Momen AA, Jelodar G, Dehdashti H. Brain magnetic resonance
imaging findings in developmentally delayed children. Int J
Pediatr. 2011;2011:386984.
17. Koul R, Al-Yahmedy M, Al-Futaisi A. Evaluation of children with
global developmental delay: a prospective study at Sultan Qaboos
University Hospital, Oman. Oman Med J. 2012;27(4):310-313.
18. Althaf Ali S, Syed NP, Murthy GSN, et al. Magnetic resonance
imaging (MRI) evaluation of developmental delay in pediatric
patients. J Clin Diagn Res. 2015;9(1):TC21-TC24.
19. Bayram E, Topcu Y, Karaoglu P, Yis U, Guleryuz HC, Kurul SH.
Incidental white matter lesions in children presenting with head-
ache. Headache. 2013;53(6):970-976.
20. Fisch N, Konen O, Halevy A, Cohen R, Shuper A. Incidental
multifocal white matter lesions in pediatric magnetic resonance
imaging. Pediatr Neurol. 2012;47(1):7-12.
21. Paul LK. Developmental malformation of the corpus callosum: a
review of typical callosal development and examples of develop-
mental disorders with callosal involvement. J Neurodev Disord.
2011;3(1):3-27.
22. Al-Hashim AH, Blaser S, Raybaud C, Macgregor D. Corpus cal-
losum abnormalities: neuroradiological and clinical correlations.
Dev Med Child Neurol. 2016;58(5):475-484.
23. Shevell MI. Clinical and diagnostic profile of agenesis of the
corpus callosum. J Child Neurol. 2002;17(12):896-900.
24. Baker LL, Barkovich AJ. The large temporal horn: MR analysis in
developmental brain anomalies versus hydrocephalus. Am J
Neuroradiol. 1992;13(1):115-122.
25. Bernasconi N, Kinay D, Andermann F, Antel S, Bernasconi A.
Analysis of shape and positioning of the hippocampal formation:
an MRI study in patients with partial epilepsy and healthy
controls. Brain. 2005;128(Pt 10):2442-2452.
26. Bajic D, Wang C, Kumlien E, et al. Incomplete inversion of the
hippocampus—a common developmental anomaly. Eur Radiol.
2008;18(1):138-142.
27. Bajic D, Kumlien E, Mattsson P, Lundberg S, Wang C, Raininko
R. Incomplete hippocampal inversion—Is there a relation to epi-
lepsy? Eur Radiol. 2009;19(10):2544-2550.
28. Cury C, Toro R, Cohen F, et al. Incomplete hippocampal inver-
sion: a comprehensive MRI study of over 2000 subjects. Front
Neuroanat. 2015;9:160.
29. Stiers P, Fonteyne A, Wouters H, D’Agostino E, Sunaert S, Lagae
L. Hippocampal malrotation in pediatric patients with epilepsy
associated with complex prefrontal dysfunction. Epilepsia. 2010;
51(4):546-555.
30. Barsi P, Kenéz J, Solymosi D, et al. Hippocampal malrotation
with normal corpus callosum: a new entity? Neuroradiology.
2000;42(5):339-345.